Prostate volume and growth in testosterone-substituted hypogonadal men are dependent on the CAG repeat polymorphism of the androgen receptor gene: A longitudinal pharmacogenetic study

Testosterone (T) substitution in hypogonadal men results in growth of the prostate gland. T effects are mediated via the androgen receptor (AR). The length of the (CAG) n polymorphism of the AR gene is negatively associated with transcriptional activity and might account for variations in prostate growth during substitution therapy. In 131 hypogonadal men aged 18 - 69 yr, we assessed prostate volume longitudinally by transrectal ultrasonography and determined AR ( CAG) n, sex hormone levels, and anthropometric measures. Sixty-nine men with primary and 62 with secondary hypogonadism began substitution therapy with im injections of T enanthate ( n = 81), transdermal T preparations ( n = 19), sc injections of human chorionic gonadotropin ( n = 17), or oral T undecanoate ( n = 14) for 2.4 +/- 0.8 yr. Average prostate size increased from 15.8 +/- 6.1 ml to 23.0 +/- 6.8 ml. ANOVA including covariates revealed initial prostate size to be dependent on age ( P < 0.001) and baseline T levels ( P = 0.01) but not on number of CAG)n ( ranging from 13 - 30; mean, 21.4 +/- 3.5). Prostate growth per year and absolute prostate size under substituted T levels ( 6.1 +/- 3.3 to 21.6 +/- 10.3 nmol/liter) were strongly dependent on ( CAG) n, with lower treatment effects in longer repeats ( both P < 0.001). Other significant predictors were initial prostate size ( negative for growth rate and positive for absolute size) and age ( positive for both growth rate and absolute size). The odds ratio for men with ( CAG) n less than 20, compared with those with ( CAG) n of 20 or more to develop a prostate size of at least 30 ml under T substitution, was 8.7 (95% confidence interval, 3.1-24.3; P< 0.001). This observation was strongly age dependent with a more pronounced odds ratio in men older than 40 yr. This first pharmacogenetic study on androgen substitution in hypogonadal men demonstrates a marked influence of the AR gene ( CAG) n polymorphism on prostate growth.